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Abstract Background The study assessed the association between COVID-19 and new-onset obstructive airway diseases, including asthma, chronic obstructive pulmonary disease, and bronchiectasis among vaccinated individuals recovering from COVID-19 during the Omicron wave. Methods This multicenter retrospective cohort study comprised 549,606 individuals from the U.S. Collaborative Network of TriNetX database, from January 8, 2022, to January 17, 2024. The hazard of new-onset obstructive airway diseases between COVID-19 and no-COVID-19 groups were compared following propensity score matching using the Kaplan–Meier method and Cox proportional hazards model. Results After propensity score matching, each group contained 274,803 participants. Patients with COVID-19 exhibited a higher risk of developing new-onset asthma than that of individuals without COVID-19 (adjusted hazard ratio (aHR), 1.27; 95% CI, 1.22–1.33; p

Abstract Background In spinal revision surgery, previous pedicle screws (PS) may need to be replaced with new implants. Failure to accurately identify the brand of PS‐based instrumentation preoperatively may increase the risk of perioperative complications. This study aimed to develop and validate an optimal deep learning (DL) model to identify the brand of PS‐based instrumentation on plain radiographs of spine (PRS) using anteroposterior (AP) and lateral images. Methods A total of 529 patients who received PS‐based instrumentation from seven manufacturers were enrolled in this retrospective study. The postoperative PRS were gathered as ground truths. The training, validation, and testing datasets contained 338, 85, and 106 patients, respectively. YOLOv5 was used to crop out the screws' trajectory, and the EfficientNet‐b0 model was used to develop single models (AP, Lateral, Merge, and Concatenated) based on the different PRS images. The ensemble models were different combinations of the single models. Primary outcomes were the models' performance in accuracy, sensitivity, precision, F1‐score, kappa value, and area under the curve (AUC). Secondary outcomes were the relative performance of models versus human readers and external validation of the DL models. Results The Lateral model had the most stable performance among single models. The discriminative performance was improved by the ensemble method. The AP + Lateral ensemble model had the most stable performance, with an accuracy of 0.9434, F1 score of 0.9388, and AUC of 0.9834. The performance of the ensemble models was comparable to that of experienced orthopedic surgeons and superior to that of inexperienced orthopedic surgeons. External validation revealed that the Lat + Concat ensemble model had the best accuracy (0.9412). Conclusion The DL models demonstrated stable performance in identifying the brand of PS‐based instrumentation based on AP and/or lateral images of PRS, which may assist orthopedic spine surgeons in preoperative revision planning in clinical practice.

This study investigates and compares the impact of different etching techniques on the fabrication of GaN high electron mobility transistors (HEMTs) between the inductively coupled plasma reactive ion etching (ICP-RIE) and the neutral beam etching (NBE) for the gate recess. By conducting direct current analysis, it was found that devices manufactured using the NBE exhibited superior electrical performance as compared with those produced using the ICP-RIE. These enhanced electrical characteristics include a transconductance of up to 100.4 mS/mm, a threshold voltage (Vth) of −2.3 V, an on/off current ratio of 1.1 × 109, a subthreshold swing (S.S.) of 99.63 mV/dec, and a remarkably low gate leakage current. Additionally, we noted varying degrees of hysteresis in the I–V characteristics were related to process disparities possibly leading to interface defects. Multi-frequency capacitance-voltage (C–V) measurements were used to identify the interface defects at the oxide/AlGaN interface of the gate. The results revealed that devices fabricated using the NBE exhibited a lower interface defect density as compared with those fabricated using the ICP-RIE, thereby elucidating the reduced hysteresis observed in the I–V characteristics. These findings indicated the significant advantages of the NBE process in the fabrication of GaN HEMTs.

The Palm-pressed mesocarp is a by-product from the palm oil mill and is comprised of 5–7 % of residual oil, which could be further refined into red palm-pressed mesocarp olein (PPMO). This study aimed to obtain the chemical profile of PPMO and assess its eye health effects through retinoid metabolic and visual cycle pathways regulation. PPMO contains exceptionally high vitamin E (1819.0 ppm) and carotenoid (1113.8 ppm) contents with a similar fatty acid composition to palm olein. The rats fed with 2 g/kg PPMO daily for 84 days through oral gavage up-regulated the retinol and retinyl palmitate levels, as well as the mRNA and protein expression levels of RBP4 in blood, CRBP1 and LRAT in the liver, RPE65 and RDH5 in the eye. The outcomes showed that PPMO showed comparable regulation effects with β-carotene in the retinoid metabolic and visual cycle pathways, revealing it as a phytonutrient-rich edible oil with beneficial eye health effects.

Abstract Given the high prevalence of clinical disease and disability among elderly individuals, there is an ever-greater demand for social care services. Despite this demand, the elder care sector has the largest labor shortage levels among all front-line providers of long-term care services. Strategies to reduce turnover and improve employee loyalty have therefore become an important issue. The purpose of this study is to identify the factors that affect the loyalty of home care workers. Following a literature review, wedetermined four independent variables—job satisfaction, work engagement, organizational citizenship behavior (OCB) and transformational leadership—and investigated their relevance to, and ability to predict, home care workers’ employee loyalty. A total of 455 home care workers participated in the anonymous survey. The results of multiple regression analysis indicate that the adjusted coefficient of determination (R 2) of the model explained 65.6% of the variance of the dependent variable, showing high explanatory capacity. The influences of the four independent variables on employee loyalty were all significant and positive, with the greatest impact on employee loyalty being exerted by OCB (Adjusted ß = 0.400), followed by job satisfaction and then transformational leadership. The three hierarchical regression models provided evidence for the partial mediating effect of job satisfaction, work engagement and OCB between transformational leadership and employee loyalty. Our findings suggest that managers of home care institutions should adopt a transformational leadership style to motivate home care workers’ job satisfaction, work engagement and OCB. Such an environment not only help retain employee but also attract more young people to join the ranks of the home care profession, which will help solve fundamental short-staffing problems.

Abstract The molecular mechanisms contributing to the regulation of Th17-mediated inflammation remain underexplored. We here report a SUMO-specific protease (SENP)2-mediated pathway induced in pathogenic Th17 cells that restricts the pathogenesis of inflammatory colitis. SENP2 regulates the maturation of small ubiquitin-like modifiers (SUMO) and recycles SUMO from the substrate proteins. We find higher levels of SENP2 in pathogenic Th17 cells. By deleting Senp2 in T-cell lineages in mice, we demonstrate that the lack of Senp2 exacerbates the severity of experimental colitis, which is linked to elevated levels of GM-CSF+IL-17A+ pathogenic Th17 cells and more severe dysbiosis of the intestinal microbiome. Adoptive transfer experiments demonstrate the cell-autonomous effect of Senp2 in restraining Th17 differentiation and colitis. The enzymatic activity of SENP2 is important for deSUMOylation of Smad4, which reduces Smad4 nuclear entry and Rorc expression. Our findings reveal a SENP2-mediated regulatory axis in the pathogenicity of Th17 cells.

ObjectiveThis study aimed to compare the stability and mechanical properties of the double chevron-cut (DCC) and biplanar (BP) distal femoral osteotomy (DFO) techniques, along with analyzing their respective contact surface areas.MethodsBiomechanical testing was performed using sawbone and 3D modeling techniques to assess axial and torsional stability, torsional stiffness, and maximum torque of both osteotomy configurations. Additionally, 3D models of the sawbone femur were created to calculate and compare the contact surface area of the DCC, BP, and conventional single-plane DFO techniques.ResultsAxial stiffness and maximum strength did not significantly differ between the two osteotomy techniques. However, in terms of torsional properties, the DCC technique exhibited superior torsional stiffness compared to the BP group (27 ± 7.7 Nm/° vs. 4.5 ± 1.5 Nm/°, p = 0.008). Although the difference in maximum torque did not reach statistical significance (63 ± 10.6 vs. 56 ± 12.1, p = 0.87), it is noteworthy that the DCC group sawbone model exhibited fracture in the shaft region instead of at the osteotomy site. Therefore, the actual maximum torque of the DCC construct may not be accurately reflected by the numerical values obtained in this study. The contact surface area analysis revealed that the BP configuration had the largest contact surface area, 111% larger than that of the single-plane configuration. but 60% of it relied on the less reliable axial cut. Conversely, the DCC osteotomy offered a 31% larger contact surface area than the single-plane configuration, with both surfaces being weight-bearing.ConclusionThe DCC osteotomy exhibited superior mechanical stability, showing improved rotational stiffness and maximum torque when compared to the BP osteotomy. Although the BP osteotomy resulted in a larger contact surface area than the DCC osteotomy, both were larger than the conventional single-plane configuration. In clinical practice, both the DCC and BP techniques should be evaluated based on patient-specific characteristics and surgical goals.

Abstract Background The purpose of this study was to apply the Predisposing, Reinforcing, and Enabling Constructs in Educational Diagnosis and Evaluation (PRECEDE) model to analyze the factors influencing preschool educators’ ability to teach health education through life skills. Methods This cross-sectional study utilized stratified random sampling and administered survey questionnaires to 503 preschool educators in public and private kindergartens in Taipei City and New Taipei City in 2019. Descriptive and hierarchical regression analyses were conducted. The PRECEDE model demonstrated a significant correlation between the enabling, reinforcing, and predisposing factors explored in this study and the preschool educators’ ability to teach health education through life skills. Results The variables explained 25% of the total variance in the ability to teach health education through life skills. When controlled in individual layers, the background variables and the enabling, reinforcing, and predisposing factors demonstrated explanatory powers of 6, 5, 7, and 7%, respectively, with respect to the ability to teach health education by utilizing life skills. Conclusions Enhancement of the enabling, reinforcing, and predisposing factors can improve preschool educators’ ability to teach health education through life skills. The support provided by the governmental policies for related training can facilitate the effective implementation of health promotion programs in kindergartens. Preschool educators must also receive on-the-job training to facilitate the effective transaction of the health education curriculum. Health classes centered on life skills in kindergartens are vital and must be incorporated into the curricula.

Skeletal stem cells residing in the suture mesenchyme are responsible for proper development, homeostasis, and injury repair of the craniofacial skeleton. These naïve cells are programmed to differentiate into osteoblast cell types and mediate bone formation via an intramembranous ossification mechanism. The simplicity of this system also offers great advantages to studying osteoblastogenesis compared to the appendicular and axial skeletons. Recent studies utilizing genetically based cell tracing have led to the identification of skeletal stem cell populations in craniofacial and body skeletons. Although the genetic analysis indicates these cells behave like stem cells in vivo, not all of them have been thoroughly examined by stem cell isolation and stem cell-mediated tissue generation. As regeneration is an integral part of stem cell characteristics, it is necessary to further analyze their ability to generate tissue at the ectopic site. The establishment of an ex vivo culture system to maintain the stemness properties for extended periods without losing the regenerative ability is also pertinent to advance our knowledge base of skeletal stem cells and their clinical applications in regenerative medicine. The purpose of this review is to discuss our recent advancements in analyses of skeletal stem cells using renal capsule transplantation and sphere culture systems.

Adult stem cells not only maintain tissue homeostasis but are also critical for tissue regeneration during injury. Skeletal stem cells are multipotent stem cells that can even generate bones and cartilage upon transplantation to an ectopic site. This tissue generation process requires essential stem cell characteristics including self-renewal, engraftment, proliferation, and differentiation in the microenvironment. Our research team has successfully characterized and isolated skeletal stem cells (SSCs) from the cranial suture called suture stem cells (SuSCs), which are responsible for craniofacial bone development, homeostasis, and injury-induced repair. To assess their stemness features, we have demonstrated the use of kidney capsule transplantation for an in vivo clonal expansion study. The results show bone formation at a single-cell level, thus permitting a faithful assessment of stem cell numbers at the ectopic site. The sensitivity in assessing stem cell presence permits using kidney capsule transplantation to determine stem cell frequency by limiting dilution assay. Here, we described detailed protocols for kidney capsule transplantation and limiting dilution assay. These methods are extremely valuable both for the evaluation of skeletogenic ability and the determination of stem cell frequency.

The ability to simultaneously modulate a set of genes for lineage-specific development has made miRNA an ideal master regulator for organogenesis. However, most miRNA deletions do not exhibit obvious phenotypic defects possibly due to functional redundancy. miRNAs are known to regulate skeletal lineages as the loss of their maturation enzyme Dicer impairs bone remodeling processes. Therefore, it is important to identify specific miRNA essential for bone homeostasis. We report the loss of MIR27a causing severe osteoporosis in mice. MIR27a affects osteoclast-mediated bone resorption but not osteoblast-mediated bone formation during skeletal remodeling. Gene profiling and bioinformatics further identify the specific targets of MIR27a in osteoclast cells. MIR27a exerts its effects on osteoclast differentiation through modulation of Squstm1/p62 whose mutations have been linked to Paget’s disease of bone. Our findings reveal a new MIR27a-p62 axis necessary and sufficient to mediate osteoclast differentiation and highlight a therapeutic implication for osteoporosis.

Incontinentia pigmenti (IP) is an X-linked dominant genodermatosis. The disease is known to be caused by recurrent deletion of exons 4–10 of the Inhibitor Of Nuclear Factor Kappa B Kinase Regulatory Subunit Gamma (IKBKG) gene located at the Xq28 chromosomal region, which encodes for NEMO/IKKgamma, a regulatory protein involved in the nuclear factor kappa B (NF-κB) signaling pathway. NF-κB plays a prominent role in the modulation of cellular proliferation, apoptosis, and inflammation. IKBKG mutation that results in a loss-of-function or dysregulated NF-κB pathway contributes to the pathophysiology of IP. Aside from typical skin characteristics such as blistering rash and wart-like skin growth presented in IP patients, other clinical manifestations like central nervous system (CNS) and ocular anomalies have also been detected. To date, the clinical genotype-phenotype correlation remains unclear due to its highly variable phenotypic expressivity. Thus, genetic findings remain an essential tool in diagnosing IP, and understanding its genetic profile allows a greater possibility for personalized treatment. IP is slowly and gradually gaining attention in research, but there is much that remains to be understood. This review highlights the progress that has been made in IP including the different types of mutations detected in various populations, current diagnostic strategies, IKBKG pathophysiology, genotype-phenotype correlation, and treatment strategies, which provide insights into understanding this rare mendelian disorder.

Biofunctional molecules with pharmacological activities are reported in various fields of application, including in the pharmaceutical, cosmetics, nutraceuticals, agriculture, and food industries [...]

Aim: The SAMe-TT2R2 score helps identify patients with atrial fibrillation (AF) likely to have poor anticoagulation control during anticoagulation with vitamin K antagonists (VKA) and those with scores >2 might be better managed with a target-specific oral anticoagulant (NOAC). We hypothesized that in clinical practice, VKAs may be prescribed less frequently to patients with AF and SAMe-TT2R2 scores >2 than to patients with lower scores. Methods and results: We analyzed the Phase III dataset of the Global Registry on Long-Term Oral Antithrombotic Treatment in Patients with Atrial Fibrillation (GLORIA-AF), a large, global, prospective global registry of patients with newly diagnosed AF and ≥1 stroke risk factor. We compared baseline clinical characteristics and antithrombotic prescriptions to determine the probability of the VKA prescription among anticoagulated patients with the baseline SAMe-TT2R2 score >2 and ≤ 2. Among 17,465 anticoagulated patients with AF, 4,828 (27.6%) patients were prescribed VKA and 12,637 (72.4%) patients an NOAC: 11,884 (68.0%) patients had SAMe-TT2R2 scores 0-2 and 5,581 (32.0%) patients had scores >2. The proportion of patients prescribed VKA was 28.0% among patients with SAMe-TT2R2 scores >2 and 27.5% in those with scores ≤2. Conclusions: The lack of a clear association between the SAMe-TT2R2 score and anticoagulant selection may be attributed to the relative efficacy and safety profiles between NOACs and VKAs as well as to the absence of trial evidence that an SAMe-TT2R2-guided strategy for the selection of the type of anticoagulation in NVAF patients has an impact on clinical outcomes of efficacy and safety. The latter hypothesis is currently being tested in a randomized controlled trial. Clinical trial registration: URL: https://www.clinicaltrials.gov//Unique identifier: NCT01937377, NCT01468701, and NCT01671007.

Skeletal stem cells residing in the suture mesenchyme are responsible for calvarial development, homeostatic maintenance, and injury-induced repair. These naïve cells exhibit long-term self-renewal, clonal expansion, and multipotency. They possess osteogenic abilities to regenerate bones in a cell-autonomous manner and can directly replace the damaged skeleton. Therefore, the establishment of reliable isolation and culturing methods for skeletal stem cells capable of preserving their stemness promises to further explore their use in cell-based therapy. Our research team is the first to isolate and purify skeletal stem cells from the calvarial suture and demonstrate their potent ability to generate bone at a single-cell level. Here, we describe detailed protocols for suture stem cell (SuSC) isolation and stemness maintenance in culture. These methods are extremely valuable for advancing our knowledge base of skeletal stem cells in craniofacial development, congenital deformity, and tissue repair and regeneration.

BackgroundEffective knowledge transfer of eLearning objects can hasten the adoption and dissemination of technology in teaching and learning. However, challenges exist which hinder inter-organisational knowledge transfer, particularly across continents. The ACoRD project aimed to transfer knowledge on digital learning development from UK/EU (provider) to Malaysian (receiver) higher education institutions (HEIs). This study explores the challenges encountered during the knowledge transfer process and lessons learned.MethodsThis is a qualitative study involving both the knowledge providers and receivers in focus group discussions (n = 25). Four focus group discussions were conducted in the early (n = 2) and mid-phase (n = 2) of the project by trained qualitative researchers using a topic guide designed to explore experiences and activities representing knowledge transfer in multi-institutional and multi-cultural settings. The interviews were audio-recorded, transcribed verbatim, and checked. The transcripts were analysed using thematic analysis.ResultsFive main themes emerged from this qualitative study: mismatched expectations between providers and receivers; acquiring new knowledge beyond the professional "comfort zone"; challenges in cascading newly acquired knowledge to colleagues and management; individual and organisational cultural differences; and disruption of knowledge transfer during the COVID-19 pandemic.ConclusionThis study highlights the need to create a conducive platform to facilitate continuous, timely and bi-directional needs assessment and feedback; this should be done in the early phase of the knowledge transfer process. The challenges and strategies identified in this study could guide more effective knowledge transfer between organisations and countries.

Leukocytoclastic vasculitis (LCV) is a systemic autoimmune disease characterized by the inflammation of the vascular endothelium. Cutaneous small vessel vasculitis (CSVV) and anti-neutrophil cytoplasmic antibodies (ANCA)-associated vasculitis (AAV) are two examples of LCV. Advancements in genomic technologies have identified risk haplotypes, genetic variants, susceptibility loci and pathways that are associated with vasculitis immunopathogenesis. The discovery of these genetic factors and their corresponding cellular signaling aberrations have enabled the development and use of novel therapeutic strategies for vasculitis. Personalized medicine aims to provide targeted therapies to individuals who show poor response to conventional interventions. For example, monoclonal antibody therapies have shown remarkable efficacy in achieving disease remission. Here, we discuss pathways involved in disease pathogenesis and the underlying genetic associations in different populations worldwide. Understanding the immunopathogenic pathways in vasculitis and identifying associated genetic variations will facilitate the development of novel and targeted personalized therapies for patients.

The new coronavirus disease (COVID-19) outbreak has challenged us to take unprecedented steps to bring this pandemic under control. In view of the urgency of this situation, convalescent plasma which was used in previous coronavirus outbreaks has emerged as one of the treatment options in this current pandemic. This is mainly due to the fact that convalescent plasma has been studied in a few case series with promising outcomes. In addition, on-going large clinical trials aimed to further evaluate the effectiveness, safety, and optimal dosage, duration and timing of administration of convalescent plasma are indeed revealing a certain level of promising results. Therefore, this article aims to provide an overview of possible mechanisms of actions of convalescent plasma, its benefits and its level of usage safeness by summarizing the existing evidence on the use of convalescent plasma in COVID-19 patients.

Na metal batteries offer compelling merits; however, the safety issue remains to be overcome. Here, the authors report an ionic liquid electrolyte based on NaCl-buffered AlCl3/[EMIm]Cl with two additives including EtAlCl2 and [EMIm]FSI which serve to stabilize SEI for reversible Na plating/stripping.

Organic/inorganic hybrid nanostructures-based dual light-detecting/gas-sensing devices were fabricated. In this research, polycrystalline perylene diimide (PDI) membrane was coated on ZnO nanorods (NRs), functioning as sensing nanocomposites. Multiple material analyses including scanning electron microscope (SEM), energy dispersive spectrometer (EDS), high resolution transmission electron microscopy (HR-TEM), X-ray diffractometer (XRD), Raman spectroscopy, and confocal laser scanning microscopy (CLSM) indicate that organic perylene diimide was successfully deposited on ZnO NRs, forming organic/inorganic membrane on the sensing device. To examine the influence of organic/inorganic hybrid nanostructure on photo-sensing and gas-sensing behaviors, UV light detection and CO gas sensing impulse response were measured. Results reveal that organic/inorganic hybrid nanostructure can effectively enhance UV light and CO gas dual-sensing properties with addition of PDI. The coating of organic PDI on the ZnO NRs not only improves the gas interaction capability and gas-sensing stability but also enhances the UV absorption efficiency. Owing to advantages of low cost, simple fabrication, compact size, and device stability, hybrid PDI/ZnO organic/inorganic light/gas dual-sensing devices are promising for future portable hazardous light and gas sensing applications.

Sophorolipids are well-known glycolipid biosurfactants, produced mainly by non-pathogenic yeast species such as Candida bombicola with high yield. Its unique environmental compatibility and high biodegradable properties have made them a focus in the present review for their promising applications in diverse areas. This study aims to examine current research trends of sophorolipids and evaluate their applications in food and health. A literature search was conducted using different research databases including PubMed, ScienceDirect, EBSCOhost, and Wiley Online Library to identify studies on the fundamental mechanisms of sophorolipids and their applications in food and health. Studies have shown that various structural forms of sophorolipids exhibit different biological and physicochemical properties. Sophorolipids represent one of the most attractive biosurfactants in the industry due to their antimicrobial action against both Gram-positive and Gram-negative microorganisms for applications in food and health sectors. In this review, we have provided an overview on the fundamental properties of sophorolipids and detailed analysis of their applications in diverse areas such as food, agriculture, pharmaceutical, cosmetic, anticancer, and antimicrobial activities.

BackgroundEngaging students in the e-learning development process enhances the effective implementation of e-learning, however, students' priority on the topics for e-learning may differ from that of the educators. This study aims to compare the differences between the students and their educators in prioritising the topics in three healthcare curricula for reusable e-learning object (RLO) development.MethodA modified Delphi study was conducted among students and educators from University Malaya (UM), Universiti Putra Malaysia (UPM) and Taylor's University (TU) on three undergraduate programmes. In Round 1, participants were asked to select the topics from the respective syllabi to be developed into RLOs. Priority ranking was determined by using frequencies and proportions. The first quartile of the prioritised topics was included in Round 2 survey, which the participants were asked to rate the level of priority of each topic using a 5-point Likert scale. The mean score of the topics was compared between students and educators.ResultA total of 43 educators and 377 students participated in this study. For UM and TU Pharmacy, there was a mismatch in the prioritised topics between the students and educators. For UPM, both the educators and students have prioritised the same topics in both rounds. To harmonise the prioritisation of topics between students and educators for UM and TU Pharmacy, the topics with a higher mean score by both the students and educators were prioritised.ConclusionThe mismatch in prioritised topics between students and educators uncovered factors that might influence the prioritisation process. This study highlighted the importance of conducting needs assessment at the beginning of eLearning resources development.

Hyaluronic acid (HA), a major component of extracellular matrix has been widely applied in pharmaceutical and cosmetic industries due to its reported pharmacological properties. Various types of HA drug delivery system including nanoparticles, cryogel-based formulations, microneedle patches, and nano-emulsions were developed. There are studies reporting that several HA-based transdermal delivery systems exhibit excellent biocompatibility, enhanced permeability and efficient localized release of anti-psoriasis drugs and have shown to inhibit psoriasis-associated skin inflammation. Similarly HA is found in abundant at epidermis of atopic dermatitis (AD) suggesting its role in atopic AD pathology. Anti-allergenic effect of atopic eczema can be achieved through the inhibition of CD44 and protein kinase C alpha (PKCα) interaction by HA. Herein, we aim to evaluate the current innovation on HA drug delivery system and the other potential applications of HA in inflammatory skin diseases, focusing on atopic dermatitis and psoriasis. HA is typically integrated into different delivery systems including nanoparticles, liposomes, ethosomes and microneedle patches in supporting drug penetration through the stratum corneum layer of the skin. For instance, ethosomes and microneedle delivery system such as curcumin-loaded HA-modified ethosomes were developed to enhance skin retention and delivery of curcumin to CD44-expressing psoriatic cells whereas methotrexate-loaded HA-based microneedle was shown to enhance skin penetration of methotrexate to alleviate psoriasis-like skin inflammation. HA-based nanoparticles and pluronic F-127 based dual responsive (pH/temperature) hydrogels had been described to enhance drug permeation through and into the intact skin for AD treatment.

Abstract The role of programmed cell death protein-1 (PD-1)/programmed cell death ligand 1 (PD-L1) in triple negative breast cancer (TNBC) remains to be fully understood. In this study, we investigated the role of PD-1 as a prognostic marker for TNBC in an Asian cohort (n = 269). Samples from patients with TNBC were labeled with antibodies against PD-L1 and PD-1, and subjected to NanoString assays to measure the expression of immune-related genes. Associations between disease-free survival (DFS), overall survival (OS) and biomarker expression were investigated. Multivariate analysis showed that tumors with high PD-1+ immune infiltrates harbored significantly increased DFS, and this increase was significant even after controlling for clinicopathological parameters (HR 0.95; P = 0.030). In addition, the density of cells expressing both CD8 and PD-1, but not the density of CD8−PD-1+ immune infiltrates, was associated with improved DFS. Notably, this prognostic significance was independent of clinicopathological parameters and the densities of total CD8+ cell (HR 0.43, P = 0.011). At the transcriptional level, high expression of PDCD1 within the tumor was significantly associated with improved DFS (HR 0.38; P = 0.027). In line with these findings, high expression of IFNG (HR 0.38; P = 0.001) and IFN signaling genes (HR 0.46; p = 0.027) was also associated with favorable DFS. Inclusion of PD-1 immune infiltrates and PDCD1 gene expression added significant prognostic value for DFS (ΔLRχ2 = 6.35; P = 0.041) and OS (ΔLRχ2 = 9.53; P = 0.008), beyond that provided by classical clinicopathological variables. Thus, PD-1 mRNA and protein expression status represent a promising, independent indicator of prognosis in TNBC.

Angelicin, a member of the furocoumarin group, is related to psoralen which is well known for its effectiveness in phototherapy. The furocoumarins as a group have been studied since the 1950s but only recently has angelicin begun to come into its own as the subject of several biological studies. Angelicin has demonstrated anti-cancer properties against multiple cell lines, exerting effects via both the intrinsic and extrinsic apoptotic pathways, and also demonstrated an ability to inhibit tubulin polymerization to a higher degree than psoralen. Besides that, angelicin too demonstrated anti-inflammatory activity in inflammatory-related respiratory and neurodegenerative ailments via the activation of NF-κB pathway. Angelicin also showed pro-osteogenesis and pro-chondrogenic effects on osteoblasts and pre-chondrocytes respectively. The elevated expression of pro-osteogenic and chondrogenic markers and activation of TGF-β/BMP, Wnt/β-catenin pathway confirms the positive effect of angelicin bone remodeling. Angelicin also increased the expression of estrogen receptor alpha (ERα) in osteogenesis. Other bioactivities, such as anti-viral and erythroid differentiating properties of angelicin, were also reported by several researchers with the latter even displaying an even greater aptitude as compared to the commonly prescribed drug, hydroxyurea, which is currently on the market. Apart from that, recently, a new application for angelicin against periodontitis had been studied, where reduction of bone loss was indirectly caused by its anti-microbial properties. All in all, angelicin appears to be a promising compound for further studies especially on its mechanism and application in therapies for a multitude of common and debilitating ailments such as sickle cell anaemia, osteoporosis, cancer, and neurodegeneration. Future research on the drug delivery of angelicin in cancer, inflammation and erythroid differentiation models would aid in improving the bioproperties of angelicin and efficacy of delivery to the targeted site. More in-depth studies of angelicin on bone remodeling, the pro-osteogenic effect of angelicin in various bone disease models and the anti-viral implications of angelicin in periodontitis should be researched. Finally, studies on the binding of angelicin toward regulatory genes, transcription factors, and receptors can be done through experimental research supplemented with molecular docking and molecular dynamics simulation.

Abstract “Carbon-based material” has demonstrated a great potential on water purification due to its strong physical adsorption to organic pollutants in the water. Three-dimensional cubic ordered mesoporous carbon (CMK-8), one of the well-known ordered mesoporous carbons, was prepared by using nanocasting method with mesoporous silica (KIT-6) as the template. In this study, CMK-8 blended with Nafion polymer to form a free-standing mesoporous CMK-8-Nafion composite membrane. The synthesis of high crystallinity CMK-8 was characterized by X-ray diffraction (XRD) and transmission electron microscopy (TEM). More than 80% methyl orange (MO) removal efficiency was observed under 254-nm UV irradiation after 120 min. Ninety-two percent recycling performance was remained after four recycling tests, which indicated a reliable servicing lifetime for the water purification. Furthermore, an additional layer of plasmonic silver nanoparticles (Ag NPs) was integrated into this CMK-8-Nafion membrane for higher pollutant removal efficiency, attributing from the generation of plasmon-resonance hot electrons from Ag NPs. A 4-in. CMK-8-Nafion composite membrane was also fabricated for the demonstration of potential large-scale utilization.

In large or massive rotator cuff tears, successful repairs are difficult and complication rates are high, because the torn tendon is contracted and the superior capsule is disrupted. Recent studies have shown that superior capsule reconstruction (SCR) in massive irreparable rotator cuff tears results in better clinical scores and preserves stable glenohumeral stability without significant complications. In this article, we propose a simple, efficient SCR technique to reinforce the repair of large or massive rotator cuff tears. For this technique, the long head of the biceps tendon is used as a local autograft for the SCR, therefore eliminating comorbidities related to graft harvesting. The proximal part of the long head of the biceps tendon is transposed posteriorly and fixed onto the footprint as the SCR, which not only can maintain the stability of the glenohumeral joint, but also can preserve the vascular supply to help healing.

Cancer, a complex yet common disease, is caused by uncontrolled cell division and abnormal cell growth due to a variety of gene mutations. Seeking effective treatments for cancer is a major research focus, as the incidence of cancer is on the rise and drug resistance to existing anti-cancer drugs is major concern. Natural products have the potential to yield unique molecules and combinations of substances that may be effective against cancer with relatively low toxicity/better side effect profile compared to standard anticancer therapy. Drug discovery work with natural products has demonstrated that natural compounds display a wide range of biological activities correlating to anticancer effects. In this review, we discuss formononetin (C16H12O4), which originates mainly from red clovers and the Chinese herb Astragalus membranaceus. The compound comes from a class of 7-hydroisoflavones with a substitution of methoxy group at position 4. Formononetin elicits antitumorigenic properties in vitro and in vivo by modulating numerous signaling pathways to induce cell apoptosis (by intrinsic pathway involving Bax, Bcl-2, and caspase-3 proteins) and cell cycle arrest (by regulating mediators like cyclin A, cyclin B1, and cyclin D1), suppress cell proliferation [by signal transducer and activator of transcription (STAT) activation, phosphatidylinositol 3-kinase/protein kinase-B (PI3K/AKT), and mitogen-activated protein kinase (MAPK) signaling pathway], and inhibit cell invasion [by regulating growth factors vascular endothelial growth factor (VEGF) and Fibroblast growth factor 2 (FGF2), and matrix metalloproteinase (MMP)-2 and MMP-9 proteins]. Co-treatment with other chemotherapy drugs such as bortezomib, LY2940002, U0126, sunitinib, epirubicin, doxorubicin, temozolomide, and metformin enhances the anticancer potential of both formononetin and the respective drugs through synergistic effect. Compiling the evidence thus far highlights the potential of formononetin to be a promising candidate for chemoprevention and chemotherapy.

Psoriasis is multifactorial disease with complex genetic predisposition. Recent advances in genetics and genomics analyses have provided many insights into the relationship between specific genetic predisposition and the immunopathological mechanisms driving psoriasis manifestation. Novel approaches which utilize array-based genotyping technologies such as genome-wide association studies and bioinformatics tools for transcriptomics analysis have identified single nucleotide polymorphisms, genes and pathways that are associated with psoriasis. The discovery of these psoriasis-associated susceptibility loci, autoimmune targets and altered signaling pathways have provided opportunities to bridge the gap of knowledge from sequence to consequence, allowing new therapeutic strategies for the treatment of psoriasis to be developed. Here, we discuss recent advances in the field by highlighting how immune functions associated with psoriasis susceptibility loci may contribute to disease pathogenesis in different populations. Understanding the genetic variations in psoriasis and how these may influence the immunological pathways to cause disease will contribute to the efforts in developing novel and targeted personalized therapies for psoriasis patients.

There are many extrinsic factors that can contribute to the premature aging of the skin. In recent years, the demand for natural cosmetic from the general population has noticeable grow. Therefore, this research aimed to investigate the bioproperties of sky fruit (Swietenia macrophylla) seed extract that could help to inhibit premature skin aging. Firstly, the extract and its fractions were tested on HaCaT cells for their wound healing properties. The presence of sky fruit’s extract and its fractions on scratch wound significantly improved cellular proliferation, migration, and closure of the wound. These effects were distinctly observed following the treatment with S. macrophylla hexane fraction (SMHF) and S. macrophylla water fraction (SMWF). Our continuous research study revealed that SMWF had antioxidant properties, which might be one of the factors contributing to its emerging wound healing properties because antioxidants are known to act as suppressors of the inflammatory pathway and aid the transition towards cell proliferation. In addition, all samples had critical wavelengths that indicated that they were able to absorb the whole UVB range and some parts of the UVA wavelength. This suggested that S. macrophylla might contain potential photoprotective bioactive compounds, which could be developed into anti-UVB photoprotective sunscreens. Thus, this warrants further studies focusing on isolation and identifications of the bioactive compounds responsible for both its photoprotective and wound healing properties. A deeper study on mechanisms of the pathways that were affected by these compounds should be conducted as well to better understand this natural product and develop it into a potential cosmeceutical ingredient.

Cardiovascular diseases (CVDs) are closely linked to cellular oxidative stress and inflammation. This may be resulted from the imbalance generation of reactive oxygen species and its role in promoting inflammation, thereby contributing to endothelial dysfunction and cardiovascular complications. Nuclear factor erythroid 2-related factor 2 (Nrf2) is a transcription factor that plays a significant role in regulating expression of antioxidant and cytoprotective enzymes in response to oxidative stress. Natural products have emerged as a potential source of bioactive compounds which have shown to protect against atherogenesis development by activating Nrf2 signaling. This review aims to provide a comprehensive summary of the published data on the function, regulation and activation of Nrf2 as well as the molecular mechanisms of natural products in regulating Nrf2 signaling. The beneficial effects of using natural bioactive compounds as a promising therapeutic approach for the prevention and treatment of CVDs are reviewed.

Background: Low lipid level is associated with better cardiovascular outcome. However, lipid paradox indicating low lipid level having worse outcomes could be seen under acute injury in some diseases. The present study was designed to clarify the prognostic significance of acute-phase lipid levels within 1 day after admission for stroke on mortality in first-ever statin-naïve acute ischemic stroke (IS) and hemorrhagic stroke (HS).Methods: This observational study was conducted using the data collected from Stroke Registry In Chang-Gung Healthcare System (SRICHS) between 2009 and 2012. Patients with recurrent stroke, onset of symptoms >1 day, and history of the use of lipid-lowering agents prior to index stroke were excluded. Stroke was classified into IS and hypertension-related HS. The primary outcomes were 30-day and 1-year mortality identified by linkage to national death registry for date and cause of death. Receiver operating characteristic (ROC) curve analysis and multivariate Cox proportional hazard models were used to examine the association of lipid profiles on admission with mortality.Results: Among the 18,268 admitted stroke patients, 3,746 IS and 465 HS patients were eligible for analysis. In IS, total cholesterol (TC)

The neuromuscular junction (NMJ) is a synapse between motoneurons and skeletal muscles to control motor behavior. Unlike extensively investigated postsynaptic differentiation, less is known about mechanisms of presynaptic assembly. Genetic evidence of Wnt in mammalian NMJ development was missing due to the existence of multiple Wnts and their receptors. We show when Wnt secretion is abolished from motoneurons by mutating the Wnt ligand secretion mediator (Wls) gene, mutant mice showed muscle weakness and neurotransmission impairment. NMJs were unstable with reduced synaptic junctional folds and fragmented AChR clusters. Nerve terminals were swollen; synaptic vesicles were fewer and mislocated. The presynaptic deficits occurred earlier than postsynaptic deficits. Intriguingly, these phenotypes were not observed when deleting Wls in muscles or Schwann cells. We identified Wnt7A and Wnt7B as major Wnts for nerve terminal development in rescue experiments. These observations demonstrate a necessary role of motoneuron Wnts in NMJ development, in particular presynaptic differentiation.

The suture mesenchyme has been postulated to act as the niche for stem cells for calvarial bones but the identity of the stem cells is unknown. Here, Maruyama et al.suggest that Axin2 expressing cells act as stem cells not only in craniofacial bone development and homeostasis but in injury-induced repair.

Bacterial foodborne pathogens are a significant health burden and the recent emergence of pathogenic resistant strains due to the excessive use of antibiotics makes it more difficult to effectively treat infections as a result of contaminated food. Awareness of this impending health crisis has spurred the search for alternative antimicrobials with natural plant antimicrobials being among the more promising candidates as these substances have good acceptability and likely low toxicity levels as they have long been used in traditional medicines. Resveratrol (3,5,4′-trihydroxystilbene) is a naturally occurring stilbenoid which has been gaining considerable attention in medical field due to its diverse biological activities - it has been reported to exhibit antioxidant, cardioprotective, anti-diabetic, anticancer, and antiaging properties. Given that resveratrol is phytoalexin, with increased synthesis in response to infection by phytopathogens, there has been interest in exploring its antimicrobial activity. This review aims to provide an overview of the published data on the antibacterial activity of resveratrol against foodborne pathogens, its mechanisms of action as well as its possible applications in food packing and processing; in addition we also summarize the current data on its potential synergism with known antibacterials and future research and applications.

Aberrant stimulation of the canonical Wnt pathway induces mammary tumorigenesis in mice. It has been well documented that two types of tumors, adenocarcinoma and adenocarcinoma with squamous metaplasia, develop in these mutants. However, the molecular mechanism underlying the induction of squamous transdifferentiation remains largely unknown. Here, we show that JNK/SAPK signaling plays an important role in Wnt-dependent mammary development and malignant transformation. The JNK/SAPK pathway is stimulated in pregnancy-mediated lobulo-alveolar morphogenesis, a process highly dependent on Wnt/β-catenin signaling. Strong elevations of JNK/SAPK signaling are associated with squamous metaplasia of the Wnt-induced adenocarcinoma. Reconstitution of β-catenin and JNK/SAPK signaling activities also promotes expression of the squamous cell marker in cultured epithelial cells. Furthermore, a synergistic activation of these two pathways can be identified in the malignant squamous cells of human endometrial and lung cancers. This is potentially a significant discovery in modern cancer therapy because of the effectiveness of an angiogenesis inhibitor, Avastin, for the treatment of adenocarcinoma, but not squamous cell carcinoma, in human lung cancers. Our finding may improve the usage of biomarkers to distinguish these two poorly differentiated tumor types, sharing similar histologic features.

Nummular headache (NH) is a newly categorized headache disorder characterized by a consistent clinicographics in each attack. Currently, it is considered as a primary headache disorder due to epicranial neuralgia but the pathomechanism is still unknown. We report a woman, whose recurrent NH subsided after trans-sphenoidal surgery for her pituitary oncocytoma. The recovery of NH in this patient encourages the central mechanism for NH occurrence. After a review of literature concerning, NH and intracranial secondaries we propose that central NH is a referral pain from pain-sensitive structures, such as meninges, superimposing by pre-existing lower pain threshold or pain modulation.

Chronic inflammation drives the development of various pathological diseases such as rheumatoid arthritis, atherosclerosis, multiple sclerosis, and cancer. The arachidonic acid pathway represents one of the major mechanisms for inflammation. Prostaglandins (PGs) are lipid products generated from arachidonic acid by the action of cyclooxygenase (COX) enzymes and their activity is blocked by nonsteroidal anti-inflammatory drugs (NSAIDS). The use of natural compounds in regulation of COX activity/prostaglandins production is receiving increasing attention. In Mediterranean diet, olive oil and table olives contain significant dietary sources of maslinic acid. Maslinic acid is arising as a safe and novel natural pentacyclic triterpene which has protective effects against chronic inflammatory diseases in various in vivo and in vitro experimental models. Understanding the anti-inflammatory mechanism of maslinic acid is crucial for its development as a potential dietary nutraceutical. This review focuses on the mechanistic action of maslinic acid in regulating the inflammation pathways through modulation of the arachidonic acid metabolism including the nuclear factor-kappa B (NF-κB)/COX-2 expression, upstream protein kinase signaling, and phospholipase A2 enzyme activity. Further investigations may provide insight into the mechanism of maslinic acid in regulating the molecular targets and their associated pathways in response to specific inflammatory stimuli.

Epidermal stratification of the mammalian skin requires proliferative basal progenitors to generate intermediate cells that separate from the basal layer and are replaced by post-mitotic cells. Although Wnt signaling has been implicated in this developmental process, the mechanism underlying Wnt-mediated regulation of basal progenitors remains elusive. Here we show that Wnt secreted from proliferative basal cells is not required for their differentiation. However, epidermal production of Wnts is essential for the formation of the spinous layer through modulation of a BMP-FGF signaling cascade in the dermis. The spinous layer defects caused by disruption of Wnt secretion can be restored by transgenically expressed Bmp4. Non-cell autonomous BMP4 promotes activation of FGF7 and FGF10 signaling, leading to an increase in proliferative basal cell population. Our findings identify an essential BMP-FGF signaling axis in the dermis that responds to the epidermal Wnts and feedbacks to regulate basal progenitors during epidermal stratification.

Post-translational modification of proteins by small ubiquitin-related modifier (SUMO) is reversible and highly evolutionarily conserved from yeasts to humans. Unlike ubiquitination with a well-established role in protein degradation, sumoylation may alter protein function, activity, stability and subcellular localization. Members of SUMO-specific protease (SENP) family, capable of SUMO removal, are involved in the reversed conjugation process. Although SUMO-specific proteases are known to reverse sumoylation in many well-defined systems, their importance in mammalian development and pathogenesis remains largely elusive. In patients with neurodegenerative diseases, aberrant accumulation of SUMO-conjugated proteins has been widely described. Several aggregation-prone proteins modulated by SUMO have been implicated in neurodegeneration, but there is no evidence supporting a direct involvement of SUMO modification enzymes in human diseases. Here we show that mice with neural-specific disruption of SENP2 develop movement difficulties which ultimately results in paralysis. The disruption induces neurodegeneration where mitochondrial dynamics is dysregulated. SENP2 regulates Drp1 sumoylation and stability critical for mitochondrial morphogenesis in an isoform-specific manner. Although dispensable for development of neural cell types, this regulatory mechanism is necessary for their survival. Our findings provide a causal link of SUMO modification enzymes to apoptosis of neural cells, suggesting a new pathogenic mechanism for neurodegeneration. Exploring the protective effect of SENP2 on neuronal cell death may uncover important preventive and therapeutic strategies for neurodegenerative diseases.

Aberrant regulation of the Wnt pathway, essential for various developmental processes, is tightly linked to human breast cancers. By hijacking this evolutionary conserved signaling pathway, cancer cells acquire sustaining proliferation ability, leading to modification of physiologic properties necessary for tumor initiation and progression. An enormous wealth of knowledge on the importance of Wnt signaling in breast development and cancer has been obtained, but the cell types responsible for production of this proliferative signal operating within normal and malignant tissues remains poorly understood. Here we report that Wnt production mediated by Gpr177 is essential for mammary morphogenesis. The loss of Gpr177 interferes with mammary stem cells, leading to deficiencies in cell proliferation and differentiation. Genetic analysis further demonstrates an indispensable role of Gpr177 in Wnt-induced tumorigenesis. The Gpr177-deficiency mice are resistant to malignant transformation. This study not only demonstrates the necessity of Wnt in mammary organogenesis but also provides a proof-of-principle for targeting of Gpr177 as a potential new treatment for human diseases with aberrant Wnt stimulation.

Axin1 and its homolog Axin2 are scaffold proteins essential for regulating Wnt signaling. Axin-dependent regulation of Wnt is important for various developmental processes and human diseases. However, the involvement of Axin1 and Axin2 in host defense and inflammation remains to be determined.Here, we report that Axin1, but not Axin2, plays an essential role in host-pathogen interaction mediated by the Wnt pathway. Pathogenic Salmonella colonization greatly reduces the level of Axin1 in intestinal epithelial cells. This reduction is regulated at the posttranslational level in early onset of the bacterial infection. Further analysis reveals that the DIX domain and Ser614 of Axin1 are necessary for the Salmonella-mediated modulation through ubiquitination and SUMOylation.Axin1 apparently has a preventive effect on bacterial invasiveness and inflammatory response during the early stages of infection. The results suggest a distinct biological function of Axin1 and Axin2 in infectious disease and intestinal inflammation while they are functionally equivalent in developmental settings.

SUMO-specific protease 2 (SENP2) modifies proteins by removing SUMO from its substrates. Although SUMO-specific proteases are known to reverse sumoylation in many defined systems, their importance in mammalian development and pathogenesis remains largely elusive. Here we report that SENP2 is highly expressed in trophoblast cells that are required for placentation. Targeted disruption of SENP2 in mice reveals its essential role in development of all three trophoblast layers. The mutation causes a deficiency in cell cycle progression. SENP2 has a specific role in the G-S transition, which is required for mitotic and endoreduplication cell cycles in trophoblast proliferation and differentiation, respectively. SENP2 ablation disturbs the p53-Mdm2 pathway, affecting the expansion of trophoblast progenitors and their maturation. Reintroducing SENP2 into the mutants can reduce the sumoylation of Mdm2, diminish the p53 level and promote trophoblast development. Furthermore, downregulation of p53 alleviates the SENP2-null phenotypes and stimulation of p53 causes abnormalities in trophoblast proliferation and differentiation, resembling those of the SENP2 mutants. Our data reveal a key genetic pathway, SENP2-Mdm2-p53, underlying trophoblast lineage development, suggesting its pivotal role in cell cycle progression of mitosis and endoreduplication.

Adult onset Still′s disease (AOSD) is a systemic inflammatory disorder of unknown etiology characterized by spiking fever, evanescent skin rash, arthralgia or arthritis, involvement of various organs, and predominantly neutrophilic leucocytosis. AOSD, although uncommon, has a characteristic constellation of clinical and laboratory features and should be considered in the differential diagnosis of pyrexia of unknown origin associated with a rash and arthralgia. The diagnosis is one of clinical suspicion and it is essential that infections, malignancy, and other rheumatic diseases are excluded. We report a case which illustrates the typical features of AOSD that were treated with steroids and azathioprine.

Abstract Background Polymerase chain reaction (PCR) ribotyping is one of the globally accepted techniques for defining epidemic clones of Clostridium difficile and tracing virulence-related strains. However, the ambiguous data generated by this technique makes it difficult to compare data attained from different laboratories; therefore, a portable technique that could supersede or supplement PCR ribotyping should be developed. The current study attempted to use a new multilocus variable-number tandem-repeat analysis (MLVA) panel to detect PCR-ribotype groups. In addition, various MLVA panels using different numbers of variable-number tandem-repeat (VNTR) loci were evaluated for their power to discriminate C. difficile clinical isolates. Results At first, 40 VNTR loci from the C. difficile genome were used to screen for the most suitable MLVA panel. MLVA and PCR ribotyping were implemented to identify 142 C. difficile isolates. Groupings of serial MLVA panels with different allelic diversity were compared with 47 PCR-ribotype groups. A MLVA panel using ten VNTR loci with limited allelic diversity (0.54-0.83), designated MLVA10, generated groups highly congruent (98%) with the PCR-ribotype groups. For comparison of discriminatory power, a MLVA panel using only four highly variable VNTR loci (allelic diversity: 0.94-0.96), designated MLVA4, was found to be the simplest MLVA panel that retained high discriminatory power. The MLVA10 and MLVA4 were combined and used to detect genetically closely related C. difficile strains. Conclusions For the epidemiological investigations of C. difficile, we recommend that MLVA10 be used in coordination with the PCR-ribotype groups to detect epidemic clones, and that the MLVA4 could be used to detect outbreak strains. MLVA10 and MLVA4 could be combined in four multiplex PCR reactions to save time and obtain distinguishable data.